European Journal of Cancer 127 (2020) 224e235

Available online at www.sciencedirect.com

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journal homepage: www.ejcancer.com

Review

Impact of colorectal cancer screening on cancer-specific

mortality in Europe: A systematic review

Andrea Gini a,*, Erik E.L. Jansen a, Nadine Zielonke a,

Reinier G.S. Meester a, Carlo Senore b, Ahti Anttila c, Nereo Segnan b,
Dominika Novak Mlakar d, Harry J. de Koning a,
Iris Lansdorp-Vogelaar a on behalf of EU-TOPIA consortium

a
Erasmus MC, University Medical Center Rotterdam, Department of Public Health, Rotterdam, the Netherlands
b
Epidemiology and Screening Unit-CPO, Città Della Salute e Della Scienza, University Hospital, Turin, Italy
c
Finnish Cancer Registry, Helsinki, Finland
d
National Institute for Public Health, Ljubljana, Slovenia

Received 11 November 2019; accepted 2 December 2019

Available online 10 January 2020

KEYWORDS Abstract Background: Populations differ with respect to their cancer risk and screening pref-
Colorectal cancer erences, which may influence the performance of colorectal cancer (CRC) screening programs.
screening; This review aims to systematically compare the mortality effect of CRC screening across Eu-
Systematic review; ropean regions.
Colorectal cancer Methods: Six databases including Embase, Medline, Web of Science, PubMed publisher, Goo-
mortality gle Scholar and Cochrane Library were searched for relevant studies published before March
2018. Bibliographic searches were conducted to select studies assessing the effect of various
screening tests (guaiac fecal occult blood test [gFOBT]; flexible sigmoidoscopy [FS]; fecal
immunochemical test [FIT] and colonoscopy) on CRC mortality in Europe (PROSPERO pro-
tocol: CRD42016042433). Abstract reviewing, data extraction and risk of bias assessment
were conducted independently by two reviewers.
Results: A total of 18 studies were included; of which, 11 were related to gFOBT, 4 to FS, 2 to
FIT and 1 to colonoscopy; 8 were randomised clinical trials, and 10, observational studies, and
an approximately equal number of studies represented Northern, Western and Southern Eu-
ropean regions. Among individuals invited to screening, CRC mortality reductions varied
from 8% to 16% for gFOBT and from 21% to 30% for FS. When studies with a high risk
of bias were considered, ranges were more extensive. The estimated effectiveness of gFOBT
and FS screening appeared similar across different European regions.

* Corresponding author: Mr. Andrea Gini, Department of Public Health, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040,
3000 CA, Rotterdam, the Netherlands, Fax: þ31(0)107038475.
E-mail address: a.gini@erasmusmc.nl (A. Gini).

https://doi.org/10.1016/j.ejca.2019.12.014
0959-8049/ª 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235
Conclusions: CRC mortality impact of inviting individuals with similar adopted screening
strategies (gFOBT or FS) may be consistent across several European settings.
ª 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Colorectal cancer (CRC) is the second and the third
leading cause of cancer death among men and women in
Europe, with more than 242,000 deaths estimated in
2018 [1]. The highest mortality rates were reported in
Eastern Europe (Hungary and Slovakia), where CRC
incidence rates have increased sharply in the last decades
owing to changes in lifestyle factors [1,2]. Screening has
the potential to reduce the burden of CRC, with the
scientific literature suggesting a reduction in CRC
mortality ranging from 18% to 57% (depending on the
screening test investigated) [3]. In 2003, the European
Council acknowledged the effectiveness of fecal occult
blood test (FOBT) screening and recommended the
implementation of organised CRC screening for men
and women aged 50e74 years in the European countries
[4].
However, CRC screening was not implemented
homogenously across Europe. Existing organised pro-
grams differed in terms of target ages, screening interval
and primary test [5]. In Finland, biennial guaiac FOBT
(gFOBT) screening is offered to men and women aged
60e69 years [6,7], whereas in France and the United
Kingdom (UK), biennial gFOBT is offered from the age
of 50 to 74 years [8,9], and in the Netherlands, Spain,
Slovenia, Ireland, Malta and Hungary, biennial fecal
immunochemical test (FIT) screening is offered in
various age ranges between 50 and 75 years [5,10e12].
CRC screening also varies within the countries, for
instance, in Italy. There, 112 regional CRC screening
programs were gradually implemented during
2003e2012, some offering the FIT and some offering
flexible sigmoidoscopy (FS) [13].
CRC screening implementation, performance and its
geographical differences are currently monitored [14].
The first European Guidelines on quality assurance in
CRC screening and diagnosis have been published,
making standards and recommendations to improve
CRC screening programmes (especially in quality
assurance and the management of detected lesions) [15].
The European Parliament has encouraged member
states to invest more in reducing screening inequalities
and stimulating early cancer diagnosis. To assist each
country in reaching these goals, the European Com-
mission funded the EU-TOPIA project (EU Framework
Programme, Horizon 2020e634753). EU-TOPIA will
systematically evaluate the harms and benefits of exist-
ing screening programs for CRC in all European
225
countries and identify ways to improve health outcomes
and reduce screening inequalities of European Union
(EU) citizens. As a first step, and to assess the appro-
priateness of various chosen screening policies, EU-
TOPIA will review the evidence of the effectiveness of
alternative screening strategies across European
countries.
In this study, we systematically reviewed the litera-
ture on the effectiveness of screening in Europe, focus-
sing on geographical disparities in the effectiveness of
screening.
2. Methods
We performed a systematic literature review
following the preferred reporting items for systematic
reviews and meta-analyses (PRISMA) statement [16].
This study was registered as part of a planned review,
and its protocol was published on 6th July 2016 in
PROSPERO (International Prospective Register of
Systematic Reviews, CRD42016042433) [17].
2.1. Literature search
Systematic bibliographic searches were conducted on
the databases Embase, Medline Ovid, Web of Science,
PubMed publisher, Google Scholar and Cochrane Li-
brary to identify potentially relevant studies. All data-
bases were searched from inception to 1st April 2016
(subsequently updated to 1st March 2018). The
computer-assisted searches were designed and per-
formed by a research librarian using controlled key-
words to assess concepts related to screening, CRC and
mortality among European countries (Appendix Tables
1a and 1b). In addition, the search was augmented with
a list of relevant, recently published, articles. All refer-
ences were managed using Thomson Reuters Endnote
X7.1, and duplicates were removed.
2.2. Study selection, data extraction and quality
assessment
Two investigators independently reviewed the titles
and abstracts of all references identified by the literature
search. A list of potential studies was retrieved consid-
ering the PICOS (population, intervention, control,
outcome and study design) criteria defined in the study
protocol (Table 1) [17]. Inclusion criteria were defined to
select relevant studies investigating the reduction in
226 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235

Table 1 each included study, the conflict of interest was reviewed

Inclusion and exclusion criteria.
Category Inclusion
Population People invited to/
participating in organised
mass screening for
colorectal cancer
Interventions Organised screening for
colorectal cancer (e.g. FS,
gFOBT, FIT,
colonoscopy)
Controls People not invited for/
participating organised
screening or people
participating in
opportunistic screening
only
Outcomes Change in mortality due to
colorectal cancer screening
(colorectal cancer
mortality reduction)
Study design Randomised controlled
trials and observational
studies, such as
prospective and
retrospective controlled
cohort studies.
Language English
gFOBT, guaiac fecal occult blood test; FIT, fecal immunochemical
test; FS, flexible sigmoidoscopy.
Exclusion
Study designs that do not
directly assess the effect of
screening.
Systematic reviews, meta-
analyses, modelling/
simulation studies, non-
original research studies
(e.g. editorials, letters) and
abstracts only.
and reported in Appendix Table 2. Eligible articles were
divided based on European areas (Northern, Western,
Southern and Eastern Europe) following the classifica-
tion provided by EUROVOC Multilingual Thesaurus of
the European Union [19]. To assess quality and bias, the
studies were evaluated using validated evaluation tools.
Randomised controlled trials (RCTs) were evaluated
using the Cochrane Library criteria for systematic re-
views of interventions and risk assessment. Observa-
tional studies were assessed using the criteria provided
by the NewcastleeOttawa Scale (NOS) [20,21]. In brief,
risk of bias was categorised as follows: ‘high risk’ was
assigned to RCTs when at least one of the Cochrane
Library criteria was assumed at high risk and to obser-
vational studies with an NOS score  4; ‘moderate risk’
was assigned to RCTs when at least one of the Cochrane
Library criteria was assumed at moderate risk and to
observational studies where the NOS score ranged from
5 to 7 and ‘low risk’ was assumed otherwise. Based on
this categorisation, the results were interpreted by both
excluding and including studies at high risk of bias to
explore the impact of quality assessment on review
conclusions. All studies were quality assessed indepen-
dently by two reviewers. Disagreements between the two
investigators were solved by consensus or consulting a
third reviewer.
3. Results

CRC mortality due to screening and focussing on pop-
ulations invited to organised CRC screening pro-
grammes. To avoid exclusion of relevant references,
studies that only reported CRC incidence reductions in
the abstract were initially not excluded. Eligible articles
were then reviewed in depth, and an additional selection
was made applying the following eligibility criteria
proposed by Elmunzer et al [3]: (i) studies in which data
or patients were duplicated in other manuscripts; (ii)
studies in which data were not reported for at least 5
years of follow-up; (iii) studies in which the total num-
ber of events and participants were not reported for each
study group or (iv) studies that assessed only the effect
on CRC incidence. From each included article, the
following data were extracted: first author; year of
publication; country where the study was conducted;
study design; screening modality; screening target pop-
ulation; follow-up information; sample size of the study
and the reported estimates (with the corresponding 95%
confidence intervals [95% CIs]) of the CRC screening
effect on cancer-specific mortality (as per the underlying
cause of death from the hospital or mortality registry,
depending on the study). Information on adjustment for
demographic differences between participants and non-
participants in screening was also extracted [18]. For
A total of 3741 citations were retrieved through the
initial searches (Fig. 1). A subsequent updated biblio-
graphic search provided 620 additional references. After
removal of duplicates, 3034 potentially relevant citations
were identified, and 70 potential articles for detailed
evaluation were selected based on the title and abstract
review. Fifty-two of these articles were excluded owing
to the eligibility criteria (Appendix Tables 3 and 4), and
thus, 18 were included in the final analysis.
The included articles varied based on the region (7
from Northern Europe, 5 from Southern and 6 from
Western), screening test assessed (11 for gFOBT, 3 for
FS, 2 for FIT, 1 for FS in combination with FIT and 1
for colonoscopy) and study design (8 RCTs, 7 cohort
studies and 3 caseecontrol studies). No studies were
retrieved from Eastern Europe.
Of the 8 RCTs, 4 assessed gFOBT (3 at low risk of
bias and one moderate, Appendix Tables 5a and 5b),
and 4 trials focused on FS (3 at low and one at high risk
of bias caused by a possible bias in the random selection
procedure, Appendix Tables 5c and 5d). Considering
observational studies, risk of bias varied from 4 to 8 out
of 9 on the NOS (Appendix Tables 6 and 7): one study
scored 4 (high risk of bias); 6 studies scored 5 or 6 and 3
studies scored 7 or 8 points.
 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235
Fig. 1. Flow chart for article search and selection process. CRC, colorectal cancer.
3.1. What is the impact of gFOBT screening across
Europe?
Effectiveness of gFOBT was investigated using various
study designs and target ages: screening was offered to
individuals between the ages 45 and 74 or 75 years in
two RCTs [22,23] and a population-based cohort study
[24], between the ages 50 and 63e74 years in three
cohort studies [9,25,26], between the ages 60 and 64e69
years in two RCTs [7,27] and for anyone older than 40
years in two caseecontrol studies [28,29]. Despite these
differences, the estimated impact of gFOBT screening
did not vary substantially across studies. Among in-
dividuals invited to screening, gFOBT screening
(participation rate ranging from 48% to 70%) decreased
their CRC mortality by 8e16% compared with that of
those not invited (Table 2, not including studies at high
risk of bias) [9,22e24,26,27]. When studies at higher risk
of bias were included, no effect on CRC mortality was
documented in Finland (relative risk [RR] Z 1.04, 95%
CI: 0.84e1.3, study at moderate risk; standardized
mortality ratio (SMR) Z 1.2, 95% CI: 0.75e1.7, at high
risk of bias; Fig. 2) [7,25].
227
For individuals participating in screening, the
reduction in CRC mortality was up to 40% [29]. How-
ever, this effect was estimated only in observational
studies (3 caseecontrol and 3 cohort studies)
[9,24,28e30] and may be confounded by demographic
differences between participants and non-participants in
screening. As shown by Libby et al [9], estimates for
cancer-specific mortality reduction adjusted for con-
founding are significantly lower (RR Z 0.83, 95% CI:
0.79e0.87) than unadjusted measures (RR Z 0.73, 95%
CI: 0.65e0.82).
3.2. What is the impact of screening with the FIT in
Europe?
Two observational studies assessed the effect of FIT
screening on CRC mortality, both from Southern
Europe (Italy; Table 1) [31,32]. Among individuals
invited to FIT screening, incidence-based CRC mortal-
ity (i.e. CRC mortality in those with a confirmed CRC
diagnosis in the local cancer registry) was 36% lower
than that among those not invited (estimated with a
maximum follow-up of 8 years) [31]. The probability of
228 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235

Table 2
Characteristics of the included studies investigating the effect of stool tests (gFOBT or FIT).
Screening/ Country Study type Participants Target Screening Follow- Participation Quality Comparison Correction RR (95% CI)
region/study age interval up rate (%) scorea provided for self- for colorectal
(years) (years) (years) selection cancer
bias mortality
gFOBT
Northern Europe
Lindholm Sweden RCT 34,144 60e64 N/Ae 9 70 A Invited vs not e 0.84 (0.71
et al [27] invited invited e0.99)
34,164 not
invitedc
Kronborg Denmark RCT 30,762 45e75 2 13.9 67 A Invited vs not e 0.84 (0.73
et al [22] invited invited e0.96)
30,966 not
invitedc
Bjerrum Denmark Cohort 166,277 50e74 Once 8.9 48 6/9 Invited vs not e 0.92 (0.86
et al [26] invited invited No e0.99)
1,240,348 Participants vs 0.77 (0.67
not invited not invited e0.90)
Pitkaniemi Finland RCT 180,210 60e69 2 4.5 69 Bg Invited vs. not e 1.04 (0.84
et al [7] invited invited e1.28)
180,282 not
invitedc
Malila et al Finland Cohort 1785 invited 50e63 N/A 9 69 4/9h Invited vs. e 1.17 (0.75
[25] control groupi e1.73)
Southern Europe
Bertario Italy Case 95 cases 40 2 N/A N/A 6/9 Participants vs No 0.64 (0.36
et al [28] econtrol (16b) non-participants e1.15)
475
controlsc
(109b)
Zappa et al Italy Case 206 cases 41 2.5 N/A N/A 5/9 Participants vs No 0.60 (0.40
[29] econtrol (46b) non-participants e0.90)
1030
controlsc
(295b)
Western Europe
Scholefield UK RCT 76,056 45e74 2 19.5 57 A Invited vs not e 0.91 (0.84
et al [23] invited invited e0.99)
75,919 not
invitedc
Libby et al UK Cohort 379,655 50e69 2 8 61 7/9 Invited vs not e 0.90 (0.83
[9] invited invited Yes e0.99)
379,655 not Participants vs No 0.83 (0.79
invited not invited e0.87)
Participants vs 0.73 (0.65
not invited e0.82)
Faivre et al France Case 178 cases 45e80 2 N/A N/A 7/9 Participants vs No 0.67 (0.48
[30] econtrol (92b) non- e0.94)
712 controls participants
(435b)
Hamza France Quasi- 45,642 45e74 2 17.3 56 6/9 Invited vs not e 0.87 (0.80
et al [24] experiment invited invited No e0.94)
45,557 not Participants vs 0.67 (0.59
invited not invited e0.76)
FIT
Southern Europe
Ventura Italy Cohort 6961 50e70 2 10.7 N/A 8/9 Participants vs No 0.59 (0.37
et al [32] participants non- e0.93)
26,285 non- participants<
participantsc
 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235 229

Table 2 (continued )
Screening/ Country Study type Participants Target Screening Follow- Participation Quality Comparison Correction RR (95% CI)
region/study age interval up rate (%) scorea provided for self- for colorectal
(years) (years) (years) selection cancer
bias mortality
Rossi et al Italy Cohort 171,785 50e74 2 8d 64 6/9 Invited vs. not e 0.64d (0.52
[31] invited invited e0.78)
(incidence-
based
mortality)d
N/A, not available; gFOBT, guaiac fecal occult blood test; FIT, fecal immunochemical test; RCT, randomised controlled trial; RR, relative risk;
CI, confidence interval; CRC, colorectal cancer; UK, United Kingdom.
Target age: ages targeted by the organised screening programme assessed in the study; follow-up: median follow-up time after initiation of the
screening programme. RR: standard mortality ratios, hazard ratios and odds ratio are presented as a RR. Screening effects estimated comparing
participants and non-participants are shown in italics.
a
Quality assessment made as per the NewcastleeOttawa Scale and Cochrane Collaboration criteria for observational studies and RCTs,
respectively; risk of bias for RCTs was categorised considering the final judgement of risk of bias as follows: A, low risk; B, moderate risk and C,
high risk.
b
Exposed to screening.
c
Controls were drawn from the same population as the intervention group.
d
Maximum follow-up, this short follow-up might have an impact on the incidence-based mortality estimates (longer survival of individuals
with screen-detected colorectal cancers).
e
Study was designed with a not-regular screening interval.
g
Limited follow-up time to assess CRC mortality reduction.
h
Lack of information regarding representativeness of the exposed cohort, selection of the non-exposed and ascertainment of the exposure.
i
General Finnish population was set as the control group.

dying from CRC was 41% lower in those who partici-
pated in FIT screening than in those who did not
participate. However, this estimate was not adjusted for
demographic differences between participants and non-
participants [32].
What is the impact of once-in-a-lifetime FS screening
across Europe?
The effect of offering FS screening was investigated by 4
RCTs (Table 3, and Fig. 3) [33e36]. Studies differed
based on screening participation (58e81%), sample size,
age at screening (from 50e55 to 64 years), enrolment
and risk of bias. The median follow-up varied from 10.9
to 21.0 years. Long-term outcomes (follow-up up to 21
years) and the effectiveness of FS in combination with
FIT screening were investigated only in Northern
Europe [33,36]. CRC mortality reductions due to once-
only FS screening ranged from 21% to 30% (point esti-
mates; among those invited compared with among those
not invited) [33e35]. When FS was offered in combi-
nation with the FIT, probability of dying from CRC was
25% lower in the invited group than in the not-invited
reference group (RR Z 0.75, 95% CI: 0.57e0.99) [33].
Among participants in the FS screening group, CRC
mortality was 38e41% lower in the invited participants
than in the not-invited control group (estimates adjusted for
demographic differences in non-participants; Fig. 3) [34,35].
3.3. What is the impact of colonoscopy in Europe?
The effect of colonoscopy screening on CRC mortality
was only evaluated in one Swiss study (Table 3) [37]. In
a closed prospective cohort study of 22,686 individuals,
the reported risk reduction for CRC death was 88%
(95% CI: 7e99%) among those who participated in
screening compared with among those who did not
participate (not adjusted for demographic differences in
non-participants).
3.4. How does the effect of CRC screening differ across
Europe?
Effectiveness of FIT and colonoscopy screening was
only investigated in a few countries, and therefore, a
direct comparison across different European regions
was not possible. For gFOBT, the effectiveness of
screening in terms of CRC reduction mortality varied
from 9% to 13% in Western Europe [9,23,24] to 16% in
Northern Europe [22,27]. For FS screening, effects on
CRC mortality varied from a 21%30% reduction across
European regions, when studies at high risk of bias were
excluded [33e35].
For individuals participating in screening (especially
with gFOBT), demographic differences between partic-
ipants and non-participants were not considered in the
effect estimations, limiting the comparison between
studies.
4. Discussion
In this systematic review, we evaluated the variation in
the effectiveness of different CRC screening strategies
across European regions. To our knowledge, no previ-
ous studies have investigated the variation in screening
effectiveness across countries, especially countries that
230 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235

Fig. 2. Impact of gFOBT and FIT screening per European region (intention-to-treat analysis). gFOBT, guaiac fecal occult blood test; FIT,
fecal immunochemical test.

share similar health goals such as EU member states. We
found that citizens invited to CRC screening in some
European countries were at lower risk of dying from
CRC than those not invited: up to 30% for FS and up to
16% for gFOBT (excluding studies with a high risk of
bias). The effect of gFOBT and sigmoidoscopy
screening varied only moderately between and within
European regions, with variations ranging from 8% to
13% in Western to 16% in Northern Europe for the ef-
fect of gFOBT; and from 21% in Northern to 30% in
Western Europe for the effect of FS. Moreover, evidence
from RCTs showed consistent results across Europe,
especially when the duration of follow-up was adequate
(>10 years).
Screening with gFOBT was mainly conducted in
Northern and Western Europe, varying in screening
target ages and reporting different screening participa-
tion rates. Participation geographically varied across
Europe, indicating a higher willingness to accept gFOBT
screening among individuals included in studies con-
ducted in Northern (67e70%) than in Western Europe
(56e61%). Nevertheless, an 8e16% reduction in CRC
mortality was found across Europe in those invited to
gFOBT screening [9,22e24,26,27], and recent
population-based cohort analyses, performed in Scot-
land and France, indicated a 10e13% lower risk of
dying from CRC [9,24]. Although two studies from
Finland showed no impact on CRC mortality in that
Table 3
Characteristics of the included studies investigating the effect of endoscopy tests (FS or colonoscopy).
Screening/ Country Study Participants Target age Screening interval Follow-up Participation Quality Comparison provided Correction for self- RR (95% CI) for
region/study type (years) (years) (years) rate (%) scorea selection bias colorectal cancer
mortality
FS
Northern Europe
Holme et al Norway RCT 10,283 invited 50e64 Once 15 61e65 A Invited vs not invited e 0.79 (0.65e0.96)
[33] to FS Invited vs not invited e FS þ FIT group: 0.75
10,289 invited (0.57e0.99)

A. Gini et al. / European Journal of Cancer 127 (2020) 224e235

to FS þ FIT
78,220 not
invitedd
Thiis- Norway RCT 400 invited 50e59 Once (colonoscopy 21.7 81 C Invited vs not invited e 0.16 (0.02e1.28)
Evensen 399 not invitedd after 13 yearsc)
et al [36]
Southern Europe
Segnan et al Italy RCT 17,136 invited 55e64 Once 11.4 58 A Invited vs not invited e 0.78 (0.56e1.08)
[35] 17,136 not Participants vs not invited Yes 0.62 (0.40e0.96)
invitedd (per-protocol analysis)
Western Europe
Atkin et al UK RCT 57,099 invited 55e64 Once 17.1 71 A Invited vs not invited e 0.70 (0.62e0.79)
[34] 112,939 not Participants vs not invited Yes 0.59 (0.49e0.70)
invitedd (per-protocol analysis)
Colonoscopy
Western Europe
Manser et al Switzerland Cohort 1912 50e80 Once 6 N/A 6/9 Participants vs non- No 0.12 (0.01e0.93)
[37] participants participants
20,774 non-
participantsd
N/A, not available; RR, relative risk; FIT, fecal immunochemical test; RCT, randomised controlled trial; RR, relative risk; CI, confidence interval; UK, United Kingdom; FS, flexible sigmoidoscopy.
Target age: ages targeted by the organised screening programme assessed in the study; follow-up: median follow-up time after initiation of the screening programme. RR: standard mortality ratios,
hazard ratios and odds ratio are presented as a RR. Screening effects estimated comparing participants and non-participants are shown in italics.
a
Quality assessment made as per the NewcastleeOttawa Scale and Cochrane Collaboration criteria for observational study and RCT,
respectively; risk of bias for RCTs was categorised considering the final judgement of risk of bias as follows: A, low risk; B, moderate risk; and C,
high risk.
c
Different screening period in the study design. (Both the control and intervention group were invited to participate in a colonoscopy
investigation.)
d
Controls were drawn from the same population as the intervention group.

231
232 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235

Fig. 3. Impact of flexible sigmoidoscopy screening per European region and the type of assessment (intention-to-treat or per-protocol
analysis). FS, flexible sigmoidoscopy.

country, the small sample size (the study at high risk,
which was conducted by Malila et al. [25]) or limited
follow-up (the study at moderate risk of bias, which was
conducted by Pitkaniemi et al. [7]) may explain those
results.A recent modeling modelling study (conducted
by Chiu et al. [38]) supported the latter explanation,
predicting a 9% CRC mortality reduction after 10 years
of follow-up for the Finnish study of Pitkaniemi et al.
For those persistently participating in gFOBT screening,
effectiveness was higher (up to 40% lower CRC mor-
tality), but this effect was mainly observed in
caseecontrol studies that did not take into consider-
ation the demographic differences between participants
and non-participants [24,28e30]. Therefore, these re-
sults may be biased and driven by other factors, such as
different underlying CRC risks or the healthy screenee
effect.
Offering FS once in a lifetime was associated with a
reduction in CRC mortality ranging from 21% to 30%
when studies at high risk of bias were excluded [33e35].
Variations in the screening participation rate and
intervention group sample size may explain the slight
 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235
difference in the effect range: compared with the UK
RCT, the Italian and Norwegian trials had fewer in-
dividuals invited and participating in FS screening
(sample size of the intervention group: 17,136e10,283
versus 57,099 individuals, respectively; participation
rate: 58e65% versus 71%, respectively) [33e35].
It is important to note that evidence of the effec-
tiveness of FS was reported only in RCTs based on
predefined populations willing to accept this screening
modality [34,35]. At this time, few population-based
organised screening programmes were implemented
using this test (Italy [Piedmont], Norway and England)
[5,39], and based on their monitoring data, FS screening
uptake was found to be lower in the unselected popu-
lation than that observed in the RCTs (i.e.  58%):
response rates varied from 29% (Italy [Turin and Ver-
ona]) to 43% (England) [40]. Nevertheless, FS has the
possibility to better detect and remove adenomatous
polyps (by participating in screening once in a life-time)
and could be superior in reducing CRC mortality
compared to at least gFOBT (if we restrict and compare
only the RCT results).
There was much less evidence for the effectiveness of
FIT and colonoscopy screening. The FIT was imple-
mented mainly in Southern and Eastern Europe (Italy,
Spain, Malta, Slovenia and Hungary) and in a few
countries in Western Europe (the Netherlands and
Ireland) [5]. However, almost all of these population-
based screening programmes were implemented rela-
tively recently, making it impossible at this point to
observe a mortality effect. Until now, the impact of the
FIT in reducing CRC mortality was only reported in
Italian studies [31,32]. Opportunistic or pilot colonos-
copy screening programmes have been implemented in
more countries [5,39] although evidence of their impact
on CRC mortality is lacking, with only one European
observational study providing information on the
beneficial effect of participating in colonoscopy
screening [37]. Three RCTs comparing FIT and colo-
noscopy screening are underway, but their results may
not be available for another 10 years [41e43].
Since 2003, the EU has recommended CRC screening
for men and women, suggesting starting and ending
gFOBT screening within the ages 50e74 years (the
effectiveness of other CRC screening modalities was not
yet assessed by RCTs at the time of the recommenda-
tion) [4]. However, in 2012, new multidisciplinary,
evidence-based European guidelines for quality assur-
ance in CRC screening were proposed, reporting that
the FIT, FS and total colonoscopy might be commonly
considered as reasonable alternatives to gFOBT
screening [44]. Our study suggests that the effect of FS
and gFOBT on CRC mortality may be consistent across
several European settings, indicating that FS screening
is more effective than gFOBT. Several studies have
highlighted the impact of FS in reducing CRC incidence
233
(another critical outcome of CRC screening) [33e35],
whereas gFOBT seems not to have had a statistically
significant effect on this outcome [23]. Although it may
be reasonable to assume a higher efficacy from endos-
copy screening than from gFOBT, the current recom-
mended stool test across Europe is the FIT, which can
achieve at least the same CRC mortality reduction as
that observed with gFOBT (or potentially similar to that
observed with FS) [31,32] but with the additional effect
on reducing CRC incidence [31,32]. Thus, policymakers
should consider test-specific effectiveness and popula-
tion preferences (such as expected participation in
screening) as the essential determinants in deciding
which CRC screening program to implement. Results
from a RCT in the Netherlands showed a far higher
initial uptake with stool tests (FIT: 61.5% and gFOBT:
49.5%) than with endoscopy investigations (FS: 32.4%)
[45]. Similarly, annual screening participation rates were
higher in Italian FIT screening programmes than in FS
(compliance in 2011: FIT, 47.1%; FS, 24.5%) [13].
Nevertheless, FS is offered once in a lifetime, whereas
screening with stool tests needs recurrent participation
over several screening rounds to achieve their expected
effects on CRC mortality. Considering initial uptake or
annual participation rates instead of cumulative uptake
over time may therefore not be appropriate [40], espe-
cially in light of the recent data showing that there were
significantly fewer regular participants than the partici-
pants in the first screening round [46e48]. In addition,
potential constraints in endoscopy resources and harms
of screening need to be considered by decision makers.
Depending on the type of screening, the demand for
endoscopy may increase substantially. Shortage of co-
lonoscopy capacity may reduce the potential benefit of
the CRC screening (especially among those with lower
social economic status). Increasing colonoscopy effi-
ciency, training and regulations may curb this demand,
but at least 10e15 years are needed to completely
overcome the shortage [49]. Furthermore, screening
might lead to the overtreatment of some precancerous
lesions that would never develop into CRC, increasing
risks of screening. In some rare cases, colonoscopy ex-
aminations could even cause severe complications or
death (especially when polypectomy is performed).
Important limitations are evident and noteworthy.
First, in assessing the effect of participating in screening,
few studies corrected their estimates to take into account
demographic differences among participants and non-
participants, therefore affecting external comparability
of their findings. Thus, any review of the effect of
participating in screening between and within European
regions may be affected by selection bias. Moreover, the
evidence of effectiveness for various screening strategies
was limited: evidence for FIT and colonoscopy
screening was available only for a few countries, and it
was impossible to compare their effectiveness across
234 A. Gini et al. / European Journal of Cancer 127 (2020) 224e235
different European regions. The impact of these
screening modalities was assessed mainly in observa-
tional studies distinguished by a selected group of in-
dividuals actively participating in screening (especially
for colonoscopy). With such designs, the results are
particularly prone to selection bias. In our review, we
included some evidence based on data collected in pe-
riods and populations with less favourable CRC sur-
vival (i.e. evidence for gFOBT screening in England and
Denmark) [50]. CRC survival has substantially
increased in the last decades owing to improvements in
surgical and medical oncology (especially in managing
rectal carcinoma) [51,52]. Thus, the effect of gFOBT on
CRC mortality may be overestimated in those studies.
Finally, this study is limited by the absence of studies
conducted in Eastern European countries. Considering
the recent GLOBOCAN estimates, CRC mortality was
higher in Central and Eastern Europe than in the Eu-
ropean average in both men and women [1]. Hence,
CRC screening could be more effective in that region
[53].
To conclude, this review highlights the beneficial ef-
fect of CRC screening across Europe. The impact on
CRC mortality of inviting individuals with screening
strategies adopting gFOBT or FS seems to be consistent
across several European settings. As a consequence, to
improve or implement CRC screening programmes,
European policymakers should carefully consider na-
tional endoscopy resources and population preferences
in conjunction with efficacy of screening modalities.
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
The authors want to thank Wichor Bramer,
biomedical information specialist at the medical library
of Erasmus Medical Centre (Rotterdam, the
Netherlands), for his valuable help, expert inputs and
solutions in the making of this systematic review. This
work was supported by the EU Framework Programme
(Horizon 2020) of the European Commission (project
reference 634753; Principal Investigator (PI): prof HJ de
Koning, MD PhD, Erasmus Medical Centre) that fun-
ded the EU-TOPIA project, of which this systematic
review is part. The funders had no influence on the
outcomes of this systematic review.
Appendix A. Supplementary data
Supplementary data to this article can be found online
at https://doi.org/10.1016/j.ejca.2019.12.014.
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